PROJECT SUMMARY - DNA-Encoded Chemistry Technology (DEC-Tec) Core The overall goals of the DNA-Encoded Chemistry Technology (DEC-Tec) Core are to use DNA-encoded small-molecule libraries to cost-effectively identify specific drug-like probes and preclinical candidates to target reproductive tract-specific proteins for a contraceptive effect, and to empower our academic biologists to translate their fundamental science into next generation non-hormonal contraceptives for men and women. The discovery of new contraceptive medicines to treat rampant population growth and prevent unplanned pregnancies is one of the most challenging scientific and healthcare problems of our time. A major roadblock is the cost to develop new medicines. The preclinical phase of drug discovery, which utilizes high-throughput screening (HTS) technologies and extensive medicinal chemistry, typically takes >4 years and cost >$20 million for each drug campaign. These costs are untenable in academia and unsustainable in industry for many therapeutic areas. To overcome this hurdle in academic drug discovery, this NIH P01 grant takes advantage of DNA-encoded chemical libraries, a unique resource available at BCM. DEC-Tec has emerged as an alternative technology for ligand discovery that addresses the limitations and economic shortcomings of HTS. DEC-Tec samples chemical space on an unprecedented scale by allowing interrogation of >1,000-fold more molecular species (1 billion compounds in our DEC-Tec libraries to date compared to 1 million compounds in the ?best? HTS collections), resulting in the direct determination of high-affinity ligands and structure?activity relationships for our contraceptive targets. In this P01 grant, our DEC-Tec Core will interrogate novel collections of 3 billion DNA-encoded drug-like molecules to identify drug-like compounds that possess physiochemical characteristics well-suited for rapid progression to preclinical evaluation. Further optimization can be achieved using our X-ray Crystallography and Drug Metabolism facilities. Our overall hypothesis is that DEC-Tec will allow us to rapidly and cost-effectively identify multiple drug-like molecules that are directed at essential spermatogenic-specific and fertilization-specific proteins, and thereby to create an assortment of unique contraceptives for men and women. The three Projects will utilize the DEC-Tec Core equally. The DEC-Tec Core will promote the concept of ?Target Action Teams? in which Project scientists work side-by-side with DEC-Tec leadership, selection scientists, chemists, and cheminformatics staff to review in vitro and in vivo findings for each drug-like molecule tested. These Target Action Teams will be accountable for designing and prosecuting the compound discovery campaign and progressing drug-like leads through additional optimization and testing. The DEC-Tec Core will provide our P01 scientists with a unique and cost- effective drug discovery resource to produce non-hormonal chemical probes and preclinical drug candidates that will positively transform the discovery of contraceptives and help to contain world-wide population growth.